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Gla-rich protein is involved in the cross-talk between calcification and inflammation in osteoarthritis

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Abstract

Osteoarthritis (OA) is a whole-joint disease characterized by articular cartilage loss, tissue inflammation, abnormal bone formation and extracellular matrix (ECM) mineralization. Disease-modifying treatments are not yet available and a better understanding of osteoarthritis pathophysiology should lead to the discovery of more effective treatments. Gla-rich protein (GRP) has been proposed to act as a mineralization inhibitor and was recently shown to be associated with OA in vivo. Here, we further investigated the association of GRP with OA mineralization–inflammation processes. Using a synoviocyte and chondrocyte OA cell system, we showed that GRP expression was up-regulated following cell differentiation throughout ECM calcification, and that inflammatory stimulation with IL-1β results in an increased expression of COX2 and MMP13 and up-regulation of GRP. Importantly, while treatment of articular cells with γ-carboxylated GRP inhibited ECM calcification, treatment with either GRP or GRP-coated basic calcium phosphate (BCP) crystals resulted in the down-regulation of inflammatory cytokines and mediators of inflammation, independently of its γ-carboxylation status. Our results strengthen the calcification inhibitory function of GRP and strongly suggest GRP as a novel anti-inflammatory agent, with potential beneficial effects on the main processes responsible for osteoarthritis progression. In conclusion, GRP is a strong candidate target to develop new therapeutic approaches.

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Acknowledgments

This work was funded by projects PTDC/SAU-ORG/112832/2009, PTDC/SAU-ORG/117266/2010 and PTDC/BIM-MEC/1168/2012, and also through Project UID/Multi/04326/2013, all from the Portuguese Science and Technology Foundation (FCT). S. Cavaco, C. S. B. Viegas and M. S. Rafael were the recipients of the FCT fellowships SFRH/BD/60867/2009, SFRH/BPD/70277/2010 and SFRH/BPD/89188/2012, respectively. Authors acknowledge the Orthopedics and Traumatology Service, Algarve Medical Centre (CHAlgarve), Faro, for providing the biological samples used in this study, and to Rheumatologic and Orthopedic Services of CHUAC for their help in obtaining cartilage samples. CIBER-BBN is a Spanish initiative from ISCIII.

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Authors and Affiliations

  1. Centre of Marine Sciences (CCMAR), University of Algarve, Campus de Gambelas, 8005-139, Faro, Portugal

    Sofia Cavaco, Carla S. B. Viegas, Marta S. Rafael & Dina C. Simes

  2. GenoGla Diagnostics, Centre of Marine Sciences (CCMAR), University of Algarve, Faro, Portugal

    Carla S. B. Viegas & Dina C. Simes

  3. Department of Orthopedics and Traumatology, Algarve Medical Centre (CHAlgarve), Faro, Portugal

    Acácio Ramos

  4. Grupo de Bioingeniería Tisular y Terapia Celular (GBTTC-CHUAC), Servicio de Reumatología, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complejo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Universidad de A Coruña (UDC), A Coruña, Spain

    Joana Magalhães & Francisco J. Blanco

  5. Centro de Investigación Biomédica en Red de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Madrid, Spain

    Joana Magalhães

  6. VitaK, Maastricht University, Maastricht, The Netherlands

    Cees Vermeer

Authors
  1. Sofia Cavaco
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  2. Carla S. B. Viegas
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  3. Marta S. Rafael
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  4. Acácio Ramos
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  5. Joana Magalhães
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  6. Francisco J. Blanco
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  7. Cees Vermeer
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  8. Dina C. Simes
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Correspondence to Dina C. Simes.

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Cavaco, S., Viegas, C.S.B., Rafael, M.S. et al. Gla-rich protein is involved in the cross-talk between calcification and inflammation in osteoarthritis. Cell. Mol. Life Sci. 73, 1051–1065 (2016). https://doi.org/10.1007/s00018-015-2033-9

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  • DOI: https://doi.org/10.1007/s00018-015-2033-9

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